Patient Selection · NICE NG28 · Clinical Frameworks

GLP-1 Receptor Agonists —
Who, When & Which Agent

A comprehensive clinical decision framework for GLP-1 RA prescribing across all licensed and emerging indications — covering NICE NG28 eligibility criteria, BMI thresholds, cardiovascular risk stratification, renal dosing adjustments, contraindications, special populations, and practical initiation checklists aligned to UK clinical practice in 2026.

S.K.H. Kazmi
Updated April 2026
NICE NG28 · SfE · KDIGO · ADA
45 min read
Overview

Who Benefits from GLP-1 RAs?

Evidence-based patient profiling across indications

GLP-1 receptor agonists now carry licensed indications across five distinct clinical domains: type 2 diabetes mellitus (glycaemic management), obesity and overweight (weight management), established cardiovascular disease with obesity (CV risk reduction — SELECT indication), chronic kidney disease with T2DM (renoprotection — emerging), and metabolic dysfunction-associated steatohepatitis (MASH — tirzepatide, regulatory review). The optimal patient for GLP-1 RA therapy is not defined by a single parameter but by a convergence of clinical, metabolic, and patient-specific factors that maximise the benefit-to-risk ratio.

5
Licensed indication domains in UK 2026
≥7%
HbA1c threshold for T2DM initiation (NICE NG28)
BMI ≥30
Primary obesity threshold (≥27 with comorbidity)
eGFR ≥15
Minimum eGFR for semaglutide with caution
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NICE NG28 February 2026 — Key Updates
NICE NG28 was updated on 18 February 2026. Medicine choice is now explicitly comorbidity-led and person-centred. The pathway distinguishes ASCVD, early-onset T2DM, obesity, CKD and frailty; subcutaneous semaglutide up to 1 mg has specific recommendations for ASCVD, while GLP-1 receptor agonists and tirzepatide have different benefit statements and stopping rules. Use the current NICE visual summary rather than applying a single HbA1c threshold to every patient.
Framework

Clinical Decision Framework

Four questions that guide prescribing across all indications

Before prescribing a GLP-1 RA, four structured clinical questions should be answered. The answers determine indication, agent choice, dose, and monitoring requirements.

1
What is the primary indication?
Is the prescribing goal primarily glycaemic control (T2DM), weight management (obesity), CV risk reduction (established CVD with obesity/T2DM), or renal protection (CKD + T2DM)? The primary indication drives drug and dose selection. Multiple indications are common — the agent with the most relevant evidence set should be prioritised (usually semaglutide or tirzepatide), with dose calibrated to the indication requiring the highest dose.
Drives drug and dose choice
2
Are there contraindications or high-risk features?
Check the product-specific UK SmPC for contraindications and warnings. Hypersensitivity is a formal contraindication for current UK semaglutide and tirzepatide products; prior pancreatitis, severe gastrointestinal disease and retinopathy require product-specific caution and monitoring rather than being presented as universal class contraindications. Assess hypoglycaemia risk with concurrent sulphonylurea or insulin and consider dose adjustment using the current SmPC and clinical judgement.
Safety screen before prescribing
3
Which agent and formulation best fits this patient?
Choose the medicine by licensed indication, comorbidities, current NICE recommendation, local formulary, product-specific safety profile and patient preference. Subcutaneous semaglutide, tirzepatide and other GLP-1 receptor agonists are not universally interchangeable or first choice in every pathway. Oral semaglutide may suit some people who prefer tablets; use the authorised brand, dose and fasting instructions for the relevant indication. Combination with insulin requires product-specific review and hypoglycaemia risk management.
Agent and formulation selection
4
What are the patient's treatment goals and preferences?
Shared decision making must address: injection preference (weekly SC vs daily oral); expected side effects (nausea, vomiting — 20–30% at initiation, usually transient); expected weight loss magnitude and timeline; cost and access (NHS formulary status vs private); need for chronic therapy (weight benefit requires indefinite continuation — STEP-4 data); and alignment with patient values regarding weight loss vs glycaemic targets. For patients ambivalent about injection therapy, frame the weekly SC injection vs daily tablet tradeoff explicitly.
Shared decision making
Indication 1

Type 2 Diabetes — Prescribing Criteria

NICE NG28 February 2026 · Treatment positioning · Drug choice

Under NICE NG28 (February 2026), GLP-1 RAs are positioned at the second-line stage of T2DM management (after metformin, or alongside metformin) and at the third-line stage (after dual therapy). However, a critical update mandates GLP-1 RAs or SGLT2 inhibitors regardless of HbA1c in patients with established atherosclerotic CVD — separating the indication into glycaemic and cardiometabolic streams.

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NICE NG28 — GLP-1 RA Eligibility in T2DM
All criteria apply · February 2026 update
✓ Definitive criteria
Stream A — Glycaemic Indication (HbA1c-driven)
  • T2DM diagnosis confirmed · Not Type 1 or MODY
  • HbA1c ≥58 mmol/mol (7.5%) despite optimised dual oral therapy (metformin + 2nd agent), OR HbA1c ≥53 mmol/mol (7.0%) with high CV risk
  • BMI ≥35 kg/m² with T2DM-related comorbidity (preferred indication — strongest weight benefit rationale), OR BMI <35 with significant weight-related consequences or injectable therapy impractical
  • Renal function adequate for chosen agent (eGFR ≥45 for exenatide; semaglutide/tirzepatide/dulaglutide usable at any eGFR with monitoring)
  • Not pregnant or planning pregnancy
Stream B — Cardiovascular Indication (irrespective of HbA1c)
  • T2DM + established atherosclerotic CVD (prior MI, stroke, PAD, or coronary revascularisation)
  • Offer GLP-1 RA or SGLT2 inhibitor regardless of current HbA1c — CV benefit is independent of glycaemic effect
  • Semaglutide (SUSTAIN-6, SELECT) or liraglutide (LEADER) preferred for CV indication — strongest evidence base
  • SGLT2i preferred if HF or CKD co-present; GLP-1 RA preferred if weight loss is a priority or SGLT2i intolerant
  • Both may be used concurrently (NICE allows combination; additive CV and renal benefits shown)
NICE NG28 Treatment Algorithm — Where GLP-1 RAs Sit
T2DM Pharmacotherapy Algorithm — NICE NG28 2026
Step 1 — Lifestyle + Metformin If HbA1c ≥48 mmol/mol (6.5%) at diagnosis HbA1c ≥53 / not at target Step 2 — Add 2nd Agent SGLT2i · SU · DPP-4i · Pioglitazone · (consider GLP-1 RA if BMI ≥35) HbA1c ≥58 / not at target Established CVD? → GLP-1 RA or SGLT2i Regardless of HbA1c Step 3 — GLP-1 RA (Preferred) or other intensification Semaglutide SC (Ozempic 0.5→1→2 mg) · Tirzepatide (Mounjaro 2.5→15 mg) Or: Dulaglutide · Oral semaglutide · Liraglutide · Exenatide XR NG28 ★ Inadequate response / HbA1c not at target Step 4 — Insulin intensification Basal insulin · Premix · Basal-bolus · Continue GLP-1 RA if weight/CV benefit Step 5 — Combination & specialist review GLP-1 RA + basal insulin · Fixed-ratio combos · Consider bariatric surgery if BMI ≥35 BMI ≥35 + T2DM → Obesity pathway (Wegovy/Zepbound) HbA1c persistently ≥86 (10%) → Basal-bolus or pump therapy NG28 KEY PRINCIPLE: For T2DM + established CVD: offer GLP-1 RA or SGLT2i at ANY HbA1c — CV benefit is independent of glycaemic effect.
Drug Choice Within the GLP-1 RA Class — T2DM
Patient characteristic
Semaglutide SC
Tirzepatide
Dulaglutide
HbA1c reduction priority
Excellent
Up to −1.8% (1 mg); −2.1% (2 mg)
Best in class
Up to −2.37–2.58% (15 mg)
Good
Up to −2.0% (4.5 mg)
Weight loss priority
Excellent
~10% at 1 mg; 15% at 2.4 mg (Wegovy)
Superior
~15–22% — greatest in class
Moderate
~4–6% — lower weight effect
Established CVD
Preferred ★
SUSTAIN-6 + SELECT superiority data
Reasonable
SURPASS-CVOT published 2025; CV superiority vs dulaglutide confirmed
Acceptable
REWIND superiority — good stroke data
CKD eGFR 25–60
Use with monitoring
FLOW data — renoprotective; no dose adjust
Caution — limited CKD data
No dedicated CKD outcomes trial yet
Use with monitoring
REWIND renal subgroup data; no dose adjust
Oral therapy preference
Rybelsus available
14 mg OD · Fasting required · ~80% of SC efficacy
SC only
No oral formulation licensed yet
SC only
No oral formulation
On basal insulin
Compatible
Add-on; reduce insulin ~20% at start
Excellent data
SURPASS-5: −2.6% HbA1c, −8.8 kg on glargine
Compatible
AWARD-9 data; reduce insulin at initiation
Prior retinopathy
Caution ⚠
SUSTAIN-6 retinopathy signal — screen first; titrate slowly
Less data
No specific retinopathy signal in trials; caution advised
Likely safer
No retinopathy signal in REWIND — may be slower HbA1c drop
NICE NG28 position
Specific NICE roles
SC semaglutide up to 1 mg has recommendation-specific roles; check pathway
Separate NICE roles
Tirzepatide has its own benefit statements and stopping rule
Alternative
When sema/tirz not tolerated or CI
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Clinical Pearl — The BMI ≥35 Rule and Its Exceptions
NICE NG28 historically specified BMI ≥35 kg/m² as the primary criterion for GLP-1 RA use in T2DM when weight management was the goal. The February 2026 update softened this to allow GLP-1 RA prescribing at BMI <35 when: (1) significant weight-related complications are present; (2) injectable therapy would be impractical without a GLP-1 RA; or (3) established CVD is present (Stream B — irrespective of BMI). For South Asian and East Asian patients, lower BMI thresholds apply (BMI ≥27.5 kg/m² equivalent to BMI ≥30 for white European populations) per the NHS England ethnicity-adjusted threshold guidance.
Indication 2

Obesity Management — Eligibility & Thresholds

Wegovy · Mounjaro · licensed indications and NICE commissioning criteria

The obesity indication in the UK operates through a separate regulatory and commissioning pathway from T2DM. Wegovy and Mounjaro are UK-authorised for weight management in eligible adults. NICE recommendations and NHS access criteria are narrower than the marketing authorisations and must be checked separately. In the UK the tirzepatide brand is Mounjaro; Zepbound is US branding.

BMI Classification & GLP-1 RA Access Thresholds (UK 2026)
Healthy Overweight Obesity I Obesity II Obesity III
25 Overweight starts
30 Wegovy eligible
35 T2DM preferred
40 Obesity III
Wegovy (UK)
BMI ≥30 kg/m²
Or BMI ≥27 with ≥1 weight-related comorbidity (HTN, T2DM, dyslipidaemia, OSA, CVD)
NHS England Tier 3
BMI ≥35 kg/m²
Or BMI ≥30 with T2DM — specialist service referral required in most areas
South/East Asian Threshold
BMI ≥27.5 kg/m²
NHS England ethnicity-adjusted threshold: equivalent metabolic risk occurs at lower BMI in South Asian populations
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Wegovy (Semaglutide 2.4 mg) — NHS Eligibility Criteria
NICE TA875 · NHS England specialist pathway · All criteria must be met
NHS licensed
NHS England access to Wegovy requires all of the following criteria to be met, assessed within a specialist tier 2/3 weight management service:
  • BMI ≥35 kg/m² OR BMI ≥30 kg/m² (≥27.5 South Asian) with ≥1 weight-related comorbidity
  • No contraindications to semaglutide (see contraindications section)
  • Engaged with specialist tier 2 or tier 3 weight management service providing lifestyle intervention
  • Prior failed attempt at non-pharmacological weight management (6-month lifestyle programme)
  • Not pregnant or planning pregnancy within 2 months (use effective contraception during treatment)
  • Adequate renal function (eGFR ≥15 — caution in severe CKD; consider alternative if ESRD)
  • Patient understands chronic therapy requirement — weight regain on discontinuation (STEP-4)
The SELECT indication (CVD without T2DM) is separately commissioned in England through the NHS England Cardiovascular Prevention programme — patients with BMI ≥27 + established CVD may access Wegovy via this pathway without requiring tier 3 specialist referral in some areas. Local commissioning arrangements vary; check local ICS formulary.
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NHS Wegovy Supply & Access 2025–2026
NHS access does not follow the marketing authorisation automatically. Tirzepatide is NICE-recommended for eligible adults under TA1026 with phased NHS England implementation; semaglutide access follows TA875 and the relevant commissioning pathway. Availability varies locally. Check the current NICE technology appraisal, NHS England implementation guidance and local formulary rather than relying on historic supply or price statements.
Indication 3

Cardiovascular Risk — SELECT Indication

Primary and secondary CV prevention · Established CVD with obesity

The SELECT trial (2023) established a new indication: cardiovascular risk reduction in people with established CVD and overweight/obesity, without diabetes. This is the first pharmacological weight-loss treatment licensed for primary CV event reduction, creating a new prescribing category that sits at the intersection of cardiology and obesity medicine.

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Semaglutide 2.4 mg — SELECT CV Indication Criteria
MHRA approved 2024 · Based on SELECT trial · n=17,604
CV Superiority ✓
  • Age ≥45 years (SELECT enrolled ≥45 yr — younger patients: apply clinical judgement)
  • BMI ≥27 kg/m² (overweight or obese; ≥25 for South/East Asian populations)
  • Established atherosclerotic CVD: prior myocardial infarction, prior ischaemic stroke, or symptomatic peripheral arterial disease
  • No diabetes mellitus (HbA1c <48 mmol/mol / <6.5% at screening) — if T2DM present, prescribe under T2DM Stream B instead
  • Willing to use as chronic therapy — CV benefit requires sustained drug exposure
Expected CV benefit: 20% relative reduction in MACE (HR 0.80), driven primarily by non-fatal MI reduction (HR 0.72). NNT ~67 over 40 months to prevent one MACE event. Absolute benefit greatest in highest-CV-risk patients (prior MI > prior stroke > PAD).
Weight loss expectation: Mean −9.4% over 104 weeks. Significant risk factor improvements (SBP −3 mmHg, lipids, CRP). 73% reduction in new-onset T2DM — may justify treatment even if primary goal is diabetes prevention in high-risk patients.
CV Risk Stratification — Which Patients Get Most Benefit?
CV Profile
Evidence level
GLP-1 RA priority
Preferred agent
T2DM + prior MI/stroke/PAD
LEADER, SUSTAIN-6, SELECT · Highest evidence
Highest ★★★
Proven mortality + MACE benefit
Semaglutide SC or tirzepatide
Obesity (no T2DM) + prior MI
SELECT · Strong RCT evidence
High ★★★
SELECT indication
Semaglutide 2.4 mg (Wegovy)
T2DM + heart failure (HFpEF)
STEP-HFpEF · Functional benefit
High ★★
KCCQ + 6MWD improvement
Semaglutide 2.4 mg (if HFpEF + obesity)
T2DM + HFrEF (EF <40%)
No specific HFrEF trial · SGLT2i superior evidence
Use with caution
SGLT2i preferred for HFrEF
Prefer SGLT2i · GLP-1 RA not contraindicated
T2DM · High risk only (no established CVD)
REWIND (69% primary prevention) · Modest evidence
Moderate ★
REWIND HR 0.98 primary prevention subgroup
Dulaglutide · Sema if also high HbA1c
Atrial fibrillation + obesity
SELECT secondary: HR 0.78 for AF burden
Emerging
Dedicated AF trial underway
Semaglutide 2.4 mg (weight-mediated AF reduction)